The burden of healthcare associated infections (HAIs) in the United States has decreased owing to evidence- based changes in practice. Preparations for introduction of Ebola Virus Disease to the U.S., however, strained the capacity of healthcare organizations, and two HAIs among healthcare workers (HCWs) showed that preparations were not fully effective. Evidence-based guidance is required for the selection and implementation of infection control and prevention precautions in anticipation of emerging and severe infectious diseases. The goal of the UIC Epicenter for Prevention of Healthcare Associated Infections is to perform basic and early translational research that will facilitate HAI prevention among patients and HCWs in the context of severe and emerging infectious diseases. Infectious patients emit pathogens into the environment, which are then transported through the environment to tissues on a susceptible person where infection may occur. Emission processes and environmental contamination, therefore, are key determinants of HAI risk through multiple routes of exposure, but the magnitude of pathogen emission and environmental load is poorly characterized. Personal protective equipment (PPE) is worn by HCWs to prevent pathogens from reaching tissues where infection may occur, but there is limited knowledge about what fraction of pathogens in the environment break-through the equipment. These represent key gaps in fundamental knowledge about HAI risk that will be addressed through the activities of the UIC Epicenter. Specifically, studies will be performed in laboratory settings with simulated healthcare activities and in healthcare settings to identify the magnitude and determinants of environmental contamination, and quantitatively test the effectiveness of different combinations of PPE. Potential combinations of PPE will be identified for testing through an inventory and broadly scoped evaluation of PPE used in healthcare and industrial settings. This information will facilitate the identification of non-PPE infection contrl and prevention interventions, meet information needs of healthcare organizations selecting PPE, and facilitate quantitative assessment of HAI risk among HCWs and patients. Informed by our findings, we will propose and conduct pilot-scale evaluation of new training content and delivery methods that will improve the preparedness of HCWs and healthcare organizations for severe and emerging infectious diseases. The outcome of this work will be generalizable knowledge and methods that can be used by healthcare organizations, government agencies and public health researchers to efficiently and systematically plan to prevent HAIs.